The purpose of thsi study was to determine the role which chronic exposure to ethanol and its metabolic product acetate play in altering some paremeters of the immune system in alcoholics and subjects with alcoholic hepatitis amd alcohlic cirrhosis. Earlier we had shown that elevation of plasma tumor necrosis factor alpha (TNF alpha) predicted death in patients with severe alcoholic hepatitis. Elevation of no other acute phase cytokine was found to do so, nor was there a correlation with standard liver function tests, nor with abstinence after discharge from 30 days in hospital. TNF alpha is secreted by monocytic-phagocitic cells and cytotoxic T lymphocytes. In order to further examine alterations in immune function in alcoholics we determined that plasma levels of interferon gamma (IFN gamma) were elevated inalcoholic subjects without clinically obvious liver disease during withdrawal from alcoholic dependence. Correlated with this elevation of IFN gamma, there was an expected increase in the expression of major histocompatibility complex (MHC) class I antigens, but a paradoxical decrease in expression of MHC class II protein on circulating mononuclear cells. Finally, it was determined that end stage renal disease patients, exposed to 1.5 mM acetate, but without exposure to ethanol as a precursor, showed acute elevation within 4 hours of circulating transforming growth factor beta (TGFbeta) during hemodialysis. TGFbeta is associated with the production of fibrosis and collagen formation, a prominent feature of alcoholic cirrhosis, while TNFalpha is associated with cell death, also a prominent feature of alcoholic cirrhosis and alcoholic hepatitis. This finding of widespread abnormalities in alcoholics begin to present a coherent pattern of alteration in immue function by ethanol and its metabolite acetate which may have clinical significance not only for our understanding of pathogenesis, but also for improved treatment if the severe and ofter fatal medical consequences of alcoholism. These findings also have implications for HIV-1 infection and progression of disease in a group of poly abusers, who also use alcohol, and constitute a high risk group for HIV-1 infection.